| Comments |
AVERAGE=Average Energy Resulting from All Group Energies. To answer questions concerning drug-receptor binding enegies, there is need to have some way
of estimating the potential bond strengths involved in the
interaction between a drug and a reasonably matched receptor,
but mechanisms for providing such estimates are
presently far from satisfactory. It is possible, for example,
to calculate the strengths of intermolecular interactions
at various levels of approximation, using perturbation
theory, but such calculations are not only time-consuming
and inaccessible to the majority of workers but also quite
unreliable in aqueous solution. For these reasons, most
medicinal chemists prefer the simpler alternative of using
standard values of the enthalpies of formation for different
types of bond (ionic, hydrogen, van der Waals, etc.) to
estimate approximate strengths for drug-receptor interaction. Again, however, there are problems with this approach, including particularly the lack of any allowance
for the entropic component of the interaction, the relatively
large range of energies associated with each type of bond,
and the uncertainty as to which of the possible bonds
associated with any drug should be included in the interaction.
To overcome these difficulties, efforts have been made
to estimate the strengths of interactions involving individual
functional groups of the drug. One approach, which
relies on finding pairs of compounds for which the difference
in binding to a receptor or enzyme may be traced
solely to the contribution of a single functional group, has
been developed by Page and Jencks (refs 5,6 in article), who refer to it as
the anchor principle. It has the major advantage that the
difference in binding of a drug molecule with, and without,
the particular functional group, incorporates only the
factors associated with that group while excluding the loss
of overall rotational and translational entropy associated
with the drug molecule (the anchor).It is limited, however,
by the requirement for many pairs of compounds that
differ only in the presence of a single functional group and
in which the role of that functional group can be traced
more or less exclusively to the provision of additional
binding energy, rather than, for example, to conformational
enhancement of biologically active forms.
In the present paper, researchers have attempted to overcome
this limitation by using a series of 200 drugs and enzyme
inhibitors, chosen somewhat subjectively on the basis of
their apparent tight binding to their corresponding receptor
sites, to provide a statistical estimate of the
strengths of noncovalent bonds associated with each
functional group in an average drug-receptor environment. See BNID 105018,105020 |